| Autor: |
Worfolk JC; Department of Biosciences, Durham University, Durham, United Kingdom., Bell S; Department of Biosciences, Durham University, Durham, United Kingdom., Simpson LD; Department of Biosciences, Durham University, Durham, United Kingdom., Carne NA; Department of Biosciences, Durham University, Durham, United Kingdom., Francis SL; Department of Biosciences, Durham University, Durham, United Kingdom., Engelbertsen V; Department of Surgery, James Cook University Hospital, Middlesbrough, United Kingdom., Brown AP; Department of Biosciences, Durham University, Durham, United Kingdom., Walker J; Department of Surgery, James Cook University Hospital, Middlesbrough, United Kingdom., Viswanath YK; Department of Surgery, James Cook University Hospital, Middlesbrough, United Kingdom., Benham AM; Department of Biosciences, Durham University, Durham, United Kingdom. |
| Abstrakt: |
Aims: AGR2 is a tissue-restricted member of the protein disulfide isomerase family that has attracted interest because it is highly expressed in a number of cancers, including gastroesophageal adenocarcinoma. The behavior of AGR2 was analyzed under oxidizing conditions, and an alkylation trapping and immunoprecipitation approach were developed to identify novel AGR2 interacting proteins. Results: The data show that AGR2 is induced in esophageal adenocarcinoma, where it participates in redox-responsive, disulfide-dependent complexes. AGR2 preferentially engages with MUC-5 as a primary client and is coexpressed with the acidic mucin in Barrett's esophagus and esophageal adenocarcinoma tissue. Innovation: New partner chaperones for AGR2 have been identified, including peroxiredoxin IV, ERp44, P5, ERp29, and Ero1α. AGR2 interacts with unexpected metabolic enzymes, including aldehyde dehydrogenase (ALDH)3A1, and engages in an alkylation-sensitive association with the autophagy receptor SQSTM1, suggesting a potential mechanism for the postendoplasmic reticulum targeting of AGR2 to mucin granules. Disulfide-driven AGR2 complex formation provides a framework for a limited number of client proteins to interact, rather than for the recruitment of multiple novel clients. Conclusion: The extended AGR2 interactome will facilitate the development of therapeutics to target AGR2/mucin pathways in esophageal cancer and other conditions, including chronic obstructive pulmonary disease. |
